Peripheral neuropathies in AIDS are prevalent, potentially disabling, often painful, and can limit the choices of life-sustaining antiretroviral therapies. Of special relevance to this Program is the light they can shed on pathogenetic mechanisms that may be shared with the CNS. Axonal degeneration, changes in the microvasculature, and prominent macrophage recruitment and activation have been found in the predominantly sensory neuropathy of AIDS (PSN), as well as in AIDS dementia. The outstanding difference is that local HIV virus replication is extremely rare in the PNS, and cannot explain the peripheral lesions or macrophage responses. This proposal addresses three fundamental pathogenetic issues: What are the macrophage and cytokine behaviors in PSN, and how could they contribute to the pathogenesis of the disorder? Are there abnormalities in the production of growth factors such as NGF, and do these reflect altered monokine production? Finally, does microangiopathy affecting the endoneurial vessels play a role in some cases of neuropathy in AIDS? All 3 Aims use shared samples and techniques, including light and EM morphometry, immunocytochemistry of fresh-frozen and fixed sliding microtome preparations, and PCR estimations of mRNA levels for macrophage products and cytokines, for growth factors and their receptors, as well as for CMV and HIV. The studies will build on our existing collection of PNS samples dissected by a standard protocol from 190 individuals dying with AIDS, including 94 cases in which samples were snap-frozen, as well as on prospective studies linked to Project I. A unifying hypothesis is that PSN may be caused or amplified by aberrated macrophage responses, including low IL-1beta production, and a consequent deficiency of nerve growth factor production. This Project is highly complementary to Project II; Projects II and III together should identify specific aspects of the immunopathology of the nervous system in AIDS that do not depend on local productive HIV infection. The analysis of growth factor production and expression of regeneration markers may also provide a rationale basis for therapeutic trials with nerve growth factor.